Chlamydia pneumoniae (TWAR) is a common human respiratory pathogen. In recent years, there has been mounting evidence showing that this organism might play a role in atherosclerosis. Because coronary heart disease is a leading cause of death in this country, the overall goal is to investigate the immunopathogenic mechanisms by which C. pneumoniae infection contributes to the development of vascular disease. The proposed studies will exploit our recent findings from mouse model studies linking C. pneumoniae infection and atherosclerosis and in vitro cell culture studies on C. pneumoniae infection of arterial wall cells. The mouse models that will be used are C57BU6 and strains derived from this background strain including, apoE-deficient and TNF-A receptor and apoE double knockout mice. Atherosclerosis in C57BU6 mice can be induced by feeding with a high fat/high cholesterol diet, while apoE mice develop atherosclerosis spontaneously on a regular diet. The specific aims are to 1) further evaluate the synergistic effect of C. pneumoniae infection and hyperlipidemia on atherogenesis by infecting mice with C. pneumoniae followed by feeding animals with a high fat/high cholesterol diet and measuring the atherosclerotic lesion development using computer assisted morphometry; 2) study the effects of C. pneumoniae infection on key components in the inflammatory process of atherosclerosis that promote atherosclerotic lesion development by recruiting lymphocytes/macrophages and eliciting inflammatory responses at lesion sites. In vitro, in vivo, and ex vivo systems will be used to assay the expression of leukocyte adhesion molecules and adherence of macrophages to the endothelial surface. The effect of TNF-A on lesion development will be investigated by infecting TNF-A receptor and apoE double knockout mice and measuring lesion development using computer assisted morphometry; 3) assess the role of macrophages in the establishment of persistent C. pneumoniae infection of atheromatous lesions using cell culture to analyze vascular cell interactions and the effect on infectivity, growth and persistence of C. pneumoniae, and characterize the growth of C. pneumoniae in macrophages loaded with low density lipoproteins (foam cells). The proposed studies should prove invaluable for understanding the disease process and developing better measures for eradication or prevention of C. pneumoniae infection and for reducing atherosclerosis and coronary heart disease.